FDA Requires PD-L1 Testing Prior to Administration of Immunotherapy Agents for Urothelial Cancer


The FDA now requires use of an approved companion diagnostic test to determine PD-L1 levels in the tumor tissue of cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer prescribed treatment with pembrolizumab (Keytruda) or atezolizumab (Tecentriq).

Jonathan E. Rosenberg, MD

Jonathan E. Rosenberg, MD

The FDA now requires use of an approved companion diagnostic test to determine PD-L1 levels in the tumor tissue of cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer prescribed treatment with pembrolizumab (Keytruda) or atezolizumab (Tecentriq). An analysis of the phase III KEYNOTE-361 and IMvigor130 trials showed that patients with low PD-L1 expression treated with either of the immunotherapy agents had poorer overall survival (OS) compared with patients treated with platinum-based chemotherapy.

Patients already receiving pembrolizumab or atezolizumab can continue treatment regardless of PD-L1 status. The agency has not changed the indications for the treatment of patients who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment.

The FDA approved the Dako PD-L1 IHC 22C3 PharmDx Assay as a companion diagnostic to select patients for pembrolizumab in August 2018. The assay uses a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells to determine PD-L1 expression. The agency requires that patients have a CPS of ≥10% to receive pembrolizumab monotherapy.

The Ventana PD-L1 (SP142) Assay won FDA approval in July 2018 as a companion diagnostic test to select patients for treatment with atezolizumab. The SP142 assay determines PD L1 expression in immune cells, and the agency requires PD-L1 stained tumor-infiltrating immune cells covering greater ≥5% of the tumor area to be eligible for atezolizumab monotherapy.

“These updates provide useful guidance regarding appropriate PD-L1 assays to be used in this patient population,” Jonathan E. Rosenberg, MD, a SITC Cancer Immunotherapy Guidelines Committee member and medical oncologist at Memorial Sloan Kettering Cancer Center, said in a release.“It is important to note that the threshold for a positive test using the Dako PD-L1 22C3 assay in urothelial cancer is different from other histologies, where the cutoffs may be lower or higher depending on the tumor type.”

The indications for both drugs remain unchanged for second-line treatment. Patients who are not eligible for treatment with any platinum-containing therapy can still receive either immunotherapy agent, regardless of PD-L1 level.

In May, the FDA issued a drug safety notification warning against the use of single-agent pembrolizumab and atezolizumab for patients with PD-L1—low expressing platinum-eligible urothelial carcinoma. A data monitoring committee (DMC) determined that patients with PD-L1–low status had decreased OS in the single-agent immunotherapy arms compared with chemotherapy in the ongoing KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) trials. KEYNOTE-361 and IMvigor130 are comparing pembrolizumab and atezolizumab, respectively, with or without chemotherapy, versus chemotherapy.

Both trials stopped enrolling patients with PD-L1—low status to the monotherapy arms. Other arms will remain open to patients with PD-L1–low tumors.

In June, the FDA restricted use of the agents in PD-L1­—low patients based on the DMC findings.

That same month, the European Medicines Agency (EMA) also recommended restricting the use of pembrolizumab and atezolizumab for this indication. The EMA determined that the PD-1/PD-L1 inhibitors reduced survival compared with chemotherapy in treatment-naïve PD-L1—low patients with locally advanced or metastatic urothelial cancer after reviewing data from Keynote-361 and IMvigor130.

The EMA recommends restricting the use of these medicines as first line-treatments for urothelial cancer. Pembrolizumab monotherapy should only be used in patients whose tumors express PD-L1 with a CPS of ≥10% and atezolizumab is reserved for patients whose tumors have a PD-L1 expression ≥5%.

The FDA previously issued accelerated approvals to both pembrolizumab and atezolizumab as frontline therapies for cisplatin-ineligible patients with metastatic urothelial carcinoma based on single-arm phase II findings, while acknowledging an overall lack of efficacy in the PD-L1—low expressing group. Investigators did observe responses in PD-L1–negative populations in these findings, and results from other phase III studies.

PD-L1 expression by CPS did not appear to affect response in the phase III KEYNOTE-045 study of pembrolizumab in platinum-pretreated patients.1The ORR in the total population was 21.1% with pembrolizumab compared with 11.4% for chemotherapy. The ORR for pembrolizumab was 21.6% compared with 6.7% for chemotherapy in patients with a CPS of ≥10%.

Among platinum-ineligible patients treated with frontline pembrolizumab in the phase II KEYNOTE-052 trial,2the ORR across all groups was 24%, which included a complete response (CR) rate of 5%. The ORR for patients with a CPS of >10% was 39%. The ORR was 20% for patients with a score between 1% and 10%, and 11% for those with a score of less than 1%. Ten of 11 CRs appeared in the ≥10% score range.

The ORR was 23%, with a CR rate of 9% in the IMvigor210 trial of frontline atezolizumab for platinum-ineligible patients.3In PD-L1 assessment via tumor infiltrating immune cell (IC), the ORR was 21% in those with an IC0 score and 21% in those with an IC1 score. ORR was 28% in the IC2/3 group and 24% across all PD-L1—positive groups (IC1/2/3).

The KEYNOTE-052 and IMvigor210 studies did not include comparator arms, but the phase II/III EORTC 30986 study showed an ORR of 41.2% for gemcitabine and carboplatin in patients with advanced platinum-ineligible urothelial carcinoma.4


  1. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma.N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.
  2. Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study.Lancet Oncol. 2017;18(11):1483-1492.
  3. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.Lancet. 2017;389(10064):67-76.
  4. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986.J Clin Oncol. 2012;30(2):191-199.
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